S207: NAVTEMADLIN, AN ORAL MDM2 INHIBITOR, ELIMINATES MYELOPROLIFERATIVE NEOPLASM-BLAST PHASE (MPN-BP) INITIATING CELLS AND PROLONGS LEUKEMIA-FREE SURVIVAL (LFS) IN AN MPN-BP PDX MODEL
Authors: Xiaoli Wang, Cing Siang Hu, Andrew Davis, Cecile Krejsa, Ronald Hoffman
Journal: HemaSphere (2023)

Background: The median overall survival of patients (pts) with MPN-BP is approximately 2.6-8.0 months (Mascarenhas 2010, 2020; Gangat 2021), highlighting the need for new treatments. We developed an MPN-BP PDX mouse model to support testing of novel therapeutic agents that can deplete MPN-BP blast cells (Wang 2022). In MPN-BP, the critical tumor suppressor p53 is inactivated due to overexpression of MDM2, a key negative regulator of the protein (Fig. 1). Navtemadlin (nvtm), a potent, selective, orally available MDM2 inhibitor (MDM2i), restores p53 activity and induces apoptosis in TP53 wild-type (TP53WT) cancer cells. Single agent nvtm demonstrated clinically meaningful and disease-modifying activity in relapsed/refractory MF patients (Al-Ali 2020; Vachhani 2021). We hypothesized nvtm would deplete/eliminate MPN-BP initiating cells and improve LFS in MPN-BP PDX mice. Aims: To test the anti-leukemia activity of nvtm in a TP53WT MPN-BP PDX model. Methods: MPN-BP PDX mice were made by transplanting 2.5-4×105 human (h) PDX spleen (SPL) cells (TP53WT with KRAS, RAD21, KMT2A, ASXL1 mutations and del[20q]) into sub-lethally irradiated NSG mice. On post-transplant day (d) 35, recipients with similar MPN-BP burden (0.16-0.39% hCD34+ blasts in peripheral blood [PB]) were treated in 21-d cycles with nvtm by oral gavage on d1-7 (50mg/kg, n=4; 75mg/kg, n=7; 100mg/kg, n=10), or with decitabine (dctb) by intraperitoneal injection 3x weekly (2.5mg/kg). Mice were monitored for LFS. Due to limited availability of MPN-BP cells, 3 experiments were conducted with the same treatment schedule, using passage (P) 3- or P4-PDX donor cells. Effects of nvtm or dctb monotherapy were assessed by leukemic cell burden (hCD45+: hCD45dimCD33+ and hCD34+ blasts) in bone marrow (BM) or SPL of treated mice vs mice receiving vehicle (veh) alone. Results: MPN-BP cells (P3 and P4) grew aggressively in recipient mice (P4, P5, respectively); all mice in veh groups died between Cycle 1 d14 - Cycle 2 d9. Nvtm treatment (75mg/kg) depleted leukemic blast numbers in BM, SPL and PB. On Cycle 1 d8: hCD45dimCD33+ blasts decreased by 96.0 ±0.1% in BM, 98.6 ±21.4% in SPL, and 100% in PB; hCD34+ blasts decreased by 98.5 ±0.05% in BM, 93.8 ±2.2% in SPL and 100% in PB (p<0.05 or p<0.001, nvtm vs. veh). Further depletion was seen on Cycle 3 d8: hCD45dimCD33+ blasts decreased by 99.2 ±0.3% in BM, 99.6 ±0.4% in SPL, and 100% in PB; hCD34+ blasts decreased by 99.46 ±0.1% in BM, 100% in SPL, and 100% in PB (p<0.001, nvtm vs. veh). By contrast, dctb resulted in small reductions in PB hCD45dimCD33+ and hCD34+ blasts (69.9% and 88.6% relative to veh, respectively) with no reductions in BM or SPL. Nvtm treatment also prolonged LFS. Mean LFS of P4-PDX mice (Fig. 2A) was 58.3d (veh); 56.3d (dctb); 86.0d (nvtm 50 mg/kg); and 90.8d (nvtm 100 mg/kg). Importantly, 2 of 3 mice treated with nvtm (75mg/kg, 3 cycles) experienced prolonged LFS, living to >1 year old without further treatment; neither hCD45dimCD33+ nor CD34+ blasts were detected upon their sacrifice due to signs of aging. Mean post-transplant LFS of P5-PDX mice was 61.8d (veh) vs. 247.7d (nvtm); p<0.03 (Fig. 2B). Adverse events were not observed in mice receiving nvtm or dctb. Summary/Conclusion: Navtemadlin eliminated hCD45dimCD33+ and hCD34+ leukemia blasts in blood and tissues, and induced long-term LFS of MPN-BP PDX mice, supporting the potential for disease-modifying treatment effects in pts with TP53WT MPN-BP.Keywords: Myeloproliferative disorder, Acute myeloid leukemia, TP53, Experimental therapeutics